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Title: Lymphoid development and function in MHC class I deficient mice
Authors: Freland, Sofia
subject: MHC class I, T cell selection, cytotoxic T lymphocyte, antigen presentation, MHC class I deficient mice, NK cell, tumor growth
Year: 3-Sep-1999
Publisher: Mikrobiologiskt och Tumörbiologiskt Centrum (MTC) / Microbiology and Tumor Biology Center (MTC)
Description: MHC class I molecules present short peptide fragments, derived from proteins synthesized in the cytosol, to specific CTL. The MHC class I molecule is a heterotrimer encompassed of a polymorphic transmembrane glycoprotein (heavy chain), ß2-microglobulin (ß2m), and a peptide. In the first study (Paper I), we carried out an in depth analysis with respect to the requirement of the ß2m and TAPtransported peptides for proper MHC class I assembly, and intracellular transport. We show that properly conformed class I heavy chains can be detected in a terminally glycosylated form indicative of cell surface expression in H-2b, H-2d and H-2s ß2m -/- ConA-stimulated splenocytes incubated at reduced temperature. Furthermore, we demonstrate the presence of Kb molecules at the surface of ß2m -/- cells cultured at 37o C. We provide evidence for a role of peptide in intracellular transport of free MHC class I heavy chains, through analysis of ConA-stimulated splenocytes from TAP1 -/-, ß2m -/- double mutant TAP1/ß2m -/- mice. Studies of MHC class I -deficient mice have also provided insights into the role of MHC class I molecules in the development of CD8+ T lymphocytes and NK cells. Although ß2m -/- mice were initially thought to be devoid of MHC class I molecules and CD8+ T cells, it is now clear that they express low levels of MHC class I molecules on the cell surface, and studies by others have provided evidence for the selection of a small pool of CD8+ T cells in these mice. The latter is true also for TAP1 -/- as well as for TAP1/ Min -/- mice. In Paper II, we addressed the ability of TAP1 -/-, ß2m -/- and TAP1/ ß2m -/- mice to mount responses against allogeneic and syngeneic MHC class I-positive tumor grafts, and against MHC class I-deficient tumor grafts. The results demonstrated a potent ability of TAP1 -/-, ß2m -/- as well as TAP1/ Win -/- mice to reject allogeneic tumors. In contrast to published data, rejection of syngeneic MHC class I expressing tumors was also observed. This response was specific for the MHC class I deficient mice. Finally, MHC class I deficient tumor grafts were accepted in MHC class I deficient mice while similar grafts were rejected in wild type mice. To directly address the potential role of CD8+ T cell responses in ß2m -/- mice, we introduced a CD8 null mutation into ß2m -/- mice (Paper III). ß2m/CD8 -/- mice and corresponding control mice were primed, and challenged with syngeneic tumor grafts. While ß2m -/- mice readily cleared such tumor grafts, similar tumor grafts grew progressively in a dose dependent manner in ß2m/CD8 -/- mice. This study provided formal proof for the dependence of CD8+ T cells in the tumor rejection responses studied. The present results suggest that studies using ß2m -/- as a model of CD8+ T cell deficiency must be regarded with caution. NK cells recognize MHC class I molecules with specific receptors. In the mouse, MHC class I-specific inhibitory receptors are dimeric C-type lectins that belong to the Ly49 family. In an attempt to re-express a functional ß2m gene in ß2m -/- mice, we generated a panel of founder mice with an unexpected mosaic expression of MHC class I molecules (Paper IV). This allowed us to study lymphocyte development in an environment where MHC class Ipositive and -negative cells had co-evolved, and to examine of the influence of MHC class I on the expression of the Ly49C inhibitory receptor on NK cells. This receptor binds to H-2Kb. It is expressed at low levels on NK cells in wild type mice of the H-2b haplotype, but at markedly higher levels on NK cells in ß2m -/- mice and other strains of mice lacking expression of H-2Kb. Through the analysis of the present MHC class I mosaic mice, we demonstrate that the expression levels of Ly49C on NK cells is a consequence not only of MHC class I expression in the environment, but also of the expression of MHC class I molecules by the NK cells themselves.
Standard no: 91-628-3714-1
Appears in Collections:Dept of Microbiology, Tumor and Cell Biology

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